DESCRIPTION: The early presence of monoaminergic projections in the developing central nervous system (CNS) suggests that these neurotransmitters may have some influence over the differentiation of neurons and the establishment of synapses. In vitro studies have shown monamine effects on developing neurons. The long-term objective of this research is to determine whether significant structural and functional changes occur in the rat area dentata after the neonatal depletion of 5-HT or norepinephrine (NE). The specific goal of the present proposal is to investigate the impact of neonatal 5-HT or NE depletion on the development of area dentata granule cells in the rat hippocampal formation. The proposed experiments will test the hypothesis that neonatal 5-HT or NE depletion will alter the morphological development of dentate granule cells particularly at the level of the perforant path synapse and that morphological changes will be reflected in electrophysiological changes in the synaptic activation of granule cells by perforant path stimulation. In the first experiment, hippocampal 5-HT or NE will be depleted by systemic administration of PCA or DSP-4 on postnatal days 3 and 4. Treated rats, rats receiving the toxins plus a monamine uptake inhibitor, rats receiving uptake inhibitor alone and saline treated controls will be studied on postnatal days 14, 21 and 60. Quantitative light microscopic studies of neurobiotin-filled granule cells and ultrastructural studies of the molecular layer will document morphological changes. In vitro electrophysiological studies will analyze the response of granule cells to perforant path stimulation. Controls for non-specific drug actions and indirect effects of monoamine depletion are included in the experimental design. The second experiment will determine whether administration of the 5-HT 1a agonist buspirone will reverse the effects of PCA treatment. The third experiment will test the 5-HT 1a antagonist NAN-190 to ascertain whether the action of this drug mimics the developmental effects of 5-HT depletion. The fourth experiment will test for a critical period for the effects of 5-HT depletion on granule cell development by administering NAN-190 for 14 days beginning on P7, P14 and P2. Buspirone and NAN-190 will be administered in a range of doses to test for dose-related changes in their effects on granule cell development. Data acquisition and analysis in the second, third and fourth experiments will be conducted as described for the first experiment. Many drugs have CNS monoaminergic effects, thus understanding the consequences of perinatal monoamine depletion in the developing CNS is an important goal.